CDKN2A Copy Number Alteration in Bladder Cancer: Integrative Analysis in Patient-Derived Xenografts and Cancer Patients

Bladder cancer (BlCa) is an extensively heterogeneous disease that leads to great variability in tumor evolution scenarios and lifelong patient surveillance, emphasizing the need for modern, minimally invasive precision medicine. Here, we explored the clinical significance fi cance of copy number alterations (CNAs) in BlCa. CNA profiling fi ling was performed in 15 patient- derived xenografts (PDXs) and validated in The Cancer Genome Atlas BlCa (TCGA-BLCA; n = 408) and Lindgren et al. (n n = 143) cohorts. CDKN2A copy number loss was identifi ed as the most frequent CNA in bladder tumors, associated with reduced CDKN2A expression, tumors of a papillary phenotype, and prolonged PDX survival. The study's ' s screening cohort consisted of 243 BlCa patients, and CDKN2A copy number was assessed in genomic DNA and cell-free DNA (cfDNA) from 217 tumors and 189 pre-treatment serum samples, respectively. CDKN2A copy number loss was correlated with superior disease-free and progression-free survival of non- muscle-invasive BlCa (NMIBC) patients. Moreover, a higher CDKN2A index ( CDKN2A/LEP ratio) in pre-treatment cfDNA was associated with advanced tumor stage and grade and shortterm NMIBC progression to invasive disease, while multivariate models fi tted for CDKN2A index in pre-treatment cfDNA offered superior risk stratification fi cation of T1/high-grade and EORTC high-risk patients, enhancing prediction of treatment outcome. CDKN2A copy number status could serve as a minimally invasive tool to improve risk stratification fi cation and support personalized prognosis in BlCa.